7. Project Summary Approximately one in three people seeking treatment for alcohol use disorder (AUD) also have major depressive disorder. These individuals use more health care resources but are twice as likely to relapse and have a greater level of disability after treatment. Consequently, the already high public health costs of AUD are likely exacerbated when other mental health problems co-occur. Further, there are no empirically supported treatments for AUD and comorbid depression, and applying an adjunct treatment for depression in comorbid cases is ineffective for reducing AUD relapse rates. This project aims to advance the science and treatment of AUD and co-occurring depression by investigating shared mechanisms across the microbiota-gut-brain axis, specifically involving digestive, immune, and cognitive processes. Disturbances to microbial species inhabiting the gut (i.e., microbiota) have been linked to alcohol use, mood, and cognitive control. Similarly, inflammatory markers and cognitive control are associated with AUD and depression. Extensive research has demonstrated that these systems are interrelated; disturbances to gut microbiota can increase circulating inflammatory markers, which then affect the brain and behavior. Thus, biological mechanisms across the microbiota-gut- brain axis may be targeted individually, or in tandem, to treat AUD and co-occurring depression. The overarching goal of this project is to identify promising treatment targets for AUD and co-occurring depression. Specifically, the research aims will investigate three components of the microbiota-gut-brain axis: (1) gut microbiota characteristics, (2) inflammatory cytokines, and (3) cognitive control. This project also aims to (4) understand how genetic factors are related to the effects of the microbiota-gut-brain axis, which has been greatly overlooked in this line of research. To achieve these research aims, this project uses data from an NIAAA-funded treatment study of AUD and an NIMH-funded study of cognitive control. Both studies have collected data across the microbiota-gut-brain axis, as well as data for examining the role of gene expression and general genetic risk. Analyses will investigate whether these mechanisms explain covariation among AUD and depressive symptoms. Further, exploratory analyses will investigate biological pathways, from gut to immune functioning, that underlie AUD and depression. The principal investigator, Dr. Ellingson, will also pursue training aims, which will broaden his skill set and enable him to (1) examine gut microbiota, (2) investigate inflammatory cytokines and other biomarkers, and (3) administer laboratory tasks of cognitive control. To guide his training and research, Dr. Ellingson has assembled a premiere mentorship team with expertise spanning the microbiota-gut-brain axis and in genetics. Thus, he will be supported as he develops skills and expertise necessary to launch a genetically informative, patient-oriented research program on biomarkers of AUD and co-occurring conditions.